Systemic Lupus Erythematosus (SLE) is a systemic disease with manifestations including arthritis, vasculitis and glomerulonephritis. Its etiology remains unkonwn, but evidence idicates that SLE is an immune complex disease and that the major pathogenic antigen-antibody system consists of DNA and antibodies to DNA. Considerable research has been done on the role of antibodies to DNA in this disease, but how antigen (DNA) becomes available to combine with antibody and thereby produce immune complexes is not understood. Moreover, while the in vivo behavior of model immune complexes containing protein antigen has been characterized, complexes containing DNA as the antigen have not been studied in vivo. The objectives of this proposal are to 1) identify factors which make DNA available for combination with anti DNA, and 2) to characterize the clearance, breakdown and tissue localization of DNA-anti DNA immune complexes of defined composition. We have shown that DNA alone is cleared from the circulation very efficiently, and that DNA-anti DNA immune complexes containing large DNA are cleared at the same rate as DNA alone. It seems unlikely, therefore, that DNA-anti DNA immune complexes can persist in the circulation. However, we have shown in vitro that some IgG DNA antibodies protect a small DNA fragment from nuclease digestion, thereby resulting in a small DNAse resistant DNA-anti DNA immune complex. We might expect these small complexes to escape normal DNA clearance mechanisms. Other DNA antibodies do not protect DNA from DNAse digestion. The clinical significance of these different antibodies, and the in vivo behavior of DNA-anti DNA complexes, has not been studied. In this grant period, we propose to complete our studies on the in vivo behavior of DNA, and to produce DNA-anti DNA immune complexes of known composition in vitro. We will use our observations on the differences between protecting and non-protecting DNA antibodies to generate a wide variety of different DNA-anti DNA complexes. Once these complexes are characterized, we will study the in vivo clearance, breakdwon, and organ deposition of DNA-anti DNA immune complexes. The results of these experiments will provide information on the behavior and pathogenicity of DNA-anti DNA immune complexes of differing composition. This information will help to define the role of DNA-anti DNA immune complexes in the pathogenesis of SLE, and potentially provide a basis for new strategies in altering the course of this disease.